The past 6 years have witnessed a dramatic reduction in HIV-associated morbidity and mortality in the developed world, an event that is generally attributed to the advent of highly active antiretroviral therapy (HAART). However, the enthusiasm generated by this therapeutic advance has been tempered by widespread reports of potentially deleterious metabolic side effects, including insulin resistance, dyslipidemia, lipoatrophy, and central fat accumulation, findings reminiscent of metabolic syndrome X and commonly referred to as HIV-associated lipodystrophy syndrome. A major goal of our laboratory has been to understand the pathogenesis of HIV-associated metabolic and morphologic abnormalities and evaluate potential therapeutic options, using a paradigm based on intensive metabolic ward assessments in which each subject serves as his or her own control. In such studies we found that a pharmacologic dose of growth hormone (GH) reduced total, trunk and visceral fat and improved lipid profiles in HIV-infected men with fat accumulation. However, GH also impaired insulin action in both muscle and liver, thus limiting its potential therapeutic value. We now propose to evaluate a novel treatment strategy using insulin-like growth factor-I (IGF-I), which has been shown to reduce fat and enhance lipid oxidation while improving insulin sensitivity, in a formulation in which it is complexed to its major binding protein, IGFBP-3, to enhance bioavailability and safety. We hypothesize that IGF-I/IGFBP-3 will achieve both fat-mobilizing and insulin-sensitizing effects in patients with HIV infection and thus provide a therapeutic advantage over GH. In the proof-of-principle study proposed in this new R21 application, we will perform intensive metabolic ward studies to evaluate the effect of three months of treatment with IGF-I/IGFBP-3 on body fat content and distribution and lean body and muscle mass (DEXA and MRI), intramyocellular lipid levels (proton spectroscopy), insulin-mediated glucose uptake and disposal (euglycemic hyperinsulinemic clamp with indirect calorimetry), oral glucose tolerance, integrated lipid and carbohydrate metabolism (stable isotope studies of glucose production, gluconeogenesis, lipolysis, de novo lipogenesis), and plasma lipid and lipoprotein levels. These studies will provide comprehensive information on the efficacy and safety this novel therapeutic approach as well as the mechanisms by which it impacts glucose and lipid metabolism in the setting of HIV infection and HAART. Should the results of this preliminary study be positive, they would provide a rationale for further studies of this agent, including a randomized, double-blind, placebo-controlled trial.